I. Field of the Invention
The invention relates to the field of molecular biology, particularly to the examination of modified LDL-immune complexes to assess human diseases including type 1 diabetes and coronary heart disease, and response to therapies therefor.
II. Related Art
In the recent decades, it has been established that atherosclerosis has a strong chronic inflammatory component (Libby, 2002; Ross, 1999; Steinberg, 2002). Under this perspective, a key issue is the definition of factors that may trigger and perpetuate the inflammatory reaction. In a multifactorial disease such as atherosclerosis, many candidates have emerged, but the understanding of their relative roles is still very incomplete. However, it is clear that modified forms of LDL are major factors in the pathogenesis of atherosclerosis. Oxidized LDL (oxLDL) has been the object of multiple studies pointing to its capacity to trigger proinflammatory events (Drake et al., 1991; Kusuhara et al., 1997; Liao et al., 1991; Quinn et al., 1987; Yla-Herttuala, 1991). This pro-inflammatory activity of oxLDL has been linked to some of the pathways associated with innate immunity (Drake et al., 1991; Liao et al., 1991; Terkeltaub et al., 1994; Hazen, 2008), but the involvement of modified LDL in pro-inflammatory immunological pathways is not limited to innate immunity pathways. There is strong evidence suggesting that adaptive cell-mediated immunity pathways are also involved in the pathogenesis of atherosclerosis (Virella and Lopes-Virella, 2008; Andersson et al., 2009). T cell activation, in turn, appears to be linked to LDL modification, because peptides derived from oxidized LDL (oxLDL) have been shown to be recognized by T cells (Stemme et al., 1995). However, the strongest link between modified LDL and innate immunity involves the activation of the humoral immune system.
Studies previously performed by the inventors examining the role of modified LDL immune complexes (mLDL-IC) in the development of cardiovascular disease in T1D included a prospective study involving 98 diabetic subjects recruited as part of the Pittsburgh EDC study that showed that modified LDL-IC, using cholesterol as a surrogate marker of modified LDL, and oxLDL antibodies, correlated with the development of coronary artery disease (CAD) over a period of seven years (Lopes-Virella et al., 1999; Orchard et al., 1999). To further evaluate the validity of the hypothesis that modified LDL play a role in the development of cardiovascular complications in T1D, the inventors screened 1050 patients from the DCCT/EDIC cohort for mLDL-IC and evaluated the impact of these IC in progression of internal and common carotid intima-medial thickness (IMT), a surrogate marker for CAD. They found that, after adjustment for age, gender, IMT at year 1, ultrasonography equipment used to measure IMT, DCCT randomization group, smoking, hypertension, HbA1c, logarithm of the albumin excretion rate (AER) and CReactive Protein (CRP) levels, mLDL-IC levels were associated with progression of internal carotid IMT (Mironova et al., 1997). However, the measurements were made using cholesterol as a surrogate marker for modified LDL and using serum samples collected after enrollment of the patients on the EDIC phase of the study, thus several years after enrollment into the DCCT. Furthermore, the samples were collected two years after the first carotid IMT measurement and 2 years before the second measurement, and therefore the predictive value of the IC could not be adequately assessed.